Antitumor compositions containing taxane derivatives

ABSTRACT

Disclosed are compositions comprising 1) taxol, taxotere, or derivatives thereof and 2) a platinum coordination complex such as cisplatin, the compositions exhibiting therapeutic synergy.

This is a division of application Ser. No. 09/371,520, filed Aug. 10,1999, which is a continuation of Ser. No. 09/182,900, filed Oct. 30,1998, now abandoned which is a divisional of application Ser. No.08/967,036, filed Nov. 10, 1997, now U.S. Pat. No. 5,908,835 which is adivisional of 08/424,470, filed May 9, 1995, now U.S. Pat. No.5,728,687, which is based on International Application No. PCTFR9301096,filed Nov. 8, 1993, which is based on French Application No. 92 13525,filed Nov. 10, 1992, all of which are incorporated herein by reference.

The present invention relates to combinations of taxol, Taxotere andtheir analogues and substances which are therapeutically useful in thetreatment of neoplastic diseases.

Taxol, Taxotere and their analogues, which possess noteworthy antitumourand antileukaemic properties, are especially useful in the treatment ofcancers of the ovary, breast or lung.

The preparation of taxol, Taxotere and their derivatives form thesubject, for example, of European Patents EP 0,253,738 and EP 0,253,739and International Application PCT WO 92/09,589.

Generally, the doses used, which depend on factors distinctive to thesubject to be treated, are between 1 and 10 mg/kg administeredintraperitoneally or between 1 and 3 mg/kg administered intravenously.

It has now been found, and this forms the subject of the presentinvention, that the efficacy of taxol, Taxotere and their analogues maybe considerably improved when they are administered in combination withat least one substance which is therapeutically useful in anticancertreatments and has a mechanism identical to or different from this oftaxane derivatives.

Among substances which may be used in association or in combination withtaxol, Taxotere or their analogues, there may be mentioned alkylatingagents such as cyclophosphamide; isosfamide, melphalan,hexamethylmelamine, thiotepa or dacarbazine, antimetabolites such aspyrimidine analogues, for instance 5-fluorouracil and cytarabine or itsanalogues such as 2-fluorodeoxycytidine, or folic acid analogues such asmethotrexate, idatrexate or trimetrexate, spindle poisons includingvinca alkaloids such as vinblastine or vincristine or their syntheticanalogues such as navelbine, or estramustine or taxoids,epidophylloptoxins such as etoposide or teniposide, antibiotics such asdaunorubicine, doxorubicin, bleomycin or mitomycin, enzymes such asL-asparaginase, topoisomerase inhibitors such as camptothecinderivatives chosen from CPT-11 and topotecan or pyridobenzoindolederivatives, and various agents such as procarbazine, mitoxantrone,platinum coordination complexes such as cisplatin or carboplatin, andbiological response modifiers or growth factor inhibitors such asinterferons or interleukins.

Moreover, since the activity of the. products depends on the doses used,it is possible to use higher doses and to increase the activity whiledecreasing the toxicity phenomena or delaying their onset by combininggrowth factors of the haematopoietic type such as G-CSF or GM-CSF orcertain interleukins with taxol, Taxotere, their analogues or theircombinations with other therapeutically active substances.

The combinations or associations according to the invention enable thephenomena of pleiotropic resistance or “multi-drug resistance” to beavoided to delayed.

More especially, the invention relates to combinations of taxol,Taxotere and their analogues with vinca alkaloids, cyclophosphamide,5-fluorouracil, doxorubicin, cisplatin and etoposide.

The improved efficacy of a combination according to the invention may bedemonstrated by determination of the therapeutic synergy.

The efficacy of a combination according to the invention may also becharacterized by adding the actions of each constituent.

A combination manifests therapeutic synergy if it is therapeuticallysuperior to one or other of the constituents used at its optimum dose[T. H. CORBETT et al., Cancer Treatment Reports, 66, 1187 (1982)].

To demonstrate the efficacy of a combination, it may be necessary tocompare the maximum tolerated dose of the combination with the maximumtolerated dose of each of the separate constituents in the study inquestion. This efficacy may be quantified, for example by the log₁₀cells killed, which is determined according to the following formula:

log₁₀cells killed=T−C (days)/3.32×T_(d)

in which T−C represents the time taken for the cells to grow, which isthe mean time in days for the tmours of the treated group (T) and thetumours of the treated group (C) to have reached a predetermined value(1 g for example) , and T_(d) represents the time in days needed for thevolume of the tumour to double in the control animals [T. H. CORBETT etal., Cancer, 40, 2660.2680 (1977); F. M. SCHABEL et al., Cancer DrugDevelopment, Part B, Methods in Cancer Research, 17, 3-51, New York,Academic Press Inc. (1979)]. A product is considered to be active iflog₁₀ cells killed is greater than or equal to 0.7. A product isconsidered to be very active if log₁₀ cells killed is greater than 2.8.

The combination, used at its own maximum tolerated dose, in which eachof the constituents will be present at a dose generally not exceedingits maximum tolerated dose, will manifest therapeutic synergy when thelog₁₀ cells killed is greater than the value of the log₁₀ cells killedof the best constituent when it is administered alone.

The efficacy of the combinations on solid tumours may be determinedexperimentally in the following manner:

The animals subjected to the experiment, generally mice, aresubcutaneously grafted bilaterally with 30 to 60 mg of a tumour fragmenton day 0. The animals bearing tumours are mixed before being subjectedto the various treatments and controls. In the case of treatment ofadvanced tumours, tumours are allowed to develop to the desired size,animals having insufficiently developed tumours being eliminated. Theselected animals are distributed at random to undergo the treatments andcontrols. Animals not bearing tumours may also be subjected to the sametreatments as the tumour-bearing animals in order to be able todissociate the toxic effect from the specific effect on the tumour.Chemotherapy generally begins from 3 to 22 days after grafting,depending on the type of tumour, and the animals are observed every day.The different animal groups are weighed 3 or 4 times a week until themaximum weight loss is attained, and the groups are then weighed atleast once a week until the end of the trial.

The tumours are measured 2 or 3 times a week until the tumour reachesapproximately 2 g, or until the animal dies if this occurs before thetumour reaches 2 g. The animals are autopsied when sacrificed.

The antitumour activity is determined in accordance with the differentparameters recorded.

For a study of the combinations on leukaemias, the animals are graftedwith a particular number of cells, and the antitumour activity isdetermined by the increase in the survival time of the treated micerelative to the controls. The product is considered to be active if theincrease in survival time is greater than 27%, and is considered to bevery active if it is greater than 75% in the case of P388 leukaemia.

The results obtained with combinations of Taxotere and variouschemotherapeutic agents, such as cyclophosphamide (alkylating agent),5-fluorouracil (antimetabolite), etoposide (semisyntheticpodophyllotoxin agent) and vincristine (vinca alkaloid), thecombinations being used at their optimum dose, are given as examples inthe following tables.

TABLE 1 Activity of the combination Taxotere + cyclophosphamide at theoptimum dose against advanced MA13/c mammary adenocarcinoma graftedsubcutaneously Dose Total log₁₀ mg/kg/injection Administration dosecells Product i.v. on days: mg/kg killed Taxotere 15 14, 17, 20 45 2.8cylcophos- 118 14 118 1.3 phamide Taxotere + 7.5 14, 17, 20, 14 22.5 3.4cyclophos- 90.0 90 phamide

TABLE 2 Activity of the combination Taxotere + etoposide at the optimumdose against early B16 melanoma grafted subcutaneously Dose Total log₁₀mg/kg/injection Administration dose cells Product i.v. on days: mg/kgkilled Taxotere 17.5 4, 7, 10, 13 70 2.8 Etoposide 46.2 4, 7, 10, 13184.8 2.8 Taxotere + 15.7 4, 7, 10, 13 62.8 4.1 etoposide 13.8(simultaneous) 55.2

TABLE 3 Activity of the combination Taxotere + 5-fluorouracil at theoptimum dose against advanced C38 colon adenocarcinoma graftedsubcutaneously Dose Total log₁₀ mg/kg/injec- Administration dose cellsProduct tion i.v. on days: mg/kg killed Taxotere 22 21, 25, 29, 33 88.01.4 5-fluorouracil 43.4 21, 25, 29, 33 173.6 1.1 Taxotere + 17.6 21, 25,29, 33 70.4 4.8 5-fluorouracil 27.0 (simultaneous) 108.0

TABLE 4 Activity of the combination Taxotere + vincristine at theoptimum dose against P388 leukaemia (10⁶ cells i.p.) Dose Total log₁₀mg/kg/injec- Administration dose cells Product tion i.v. on days: mg/kgkilled Taxotere 17.5 4, 7, 10, 13 70 2.8 vincristine 46.2 4, 7, 10, 13184.8 2.8 Taxotere + 21.75 1, 4, 7 65.25 62 vincristine 1.2(simultaneous) 3.6 Taxotere + 21.75 1, 4, 7 65.25 77 vincristine 1.2 (4hours 3.6 apart)

The present invention also relates to pharmaceutical compositionscontaining the combinations according to the invention.

The products of which the combination are composed may be administeredsimultaneously, separately or spaced out over a period of time so as toobtain the maximum efficacy of the combination; it being possible foreach administration to vary in its duration from a rapid administrationto a continuous perfusion.

As a result, for the purposes of the present invention, the combinationsare not exclusively limited to those which are obtained by physicalassociation of the constituents, but also to those which permit aseparate administration, which can be simultaneous or spaced out over aperiod of time.

The compositions according to the invention are preferably compositionswhich can be administered parentally. However, these compositions may beadministered orally or intraperitoneally in the case of localizedregional therapies.

The compositions for parental administration are generallypharmaceutically acceptable, sterile solutions or suspensions which mayoptionally be prepared as required at the time of use. For thepreparation of non-aqueous solutions or suspensions, natural vegetableoils such as-olive oil, sesame oil or liquid petroleum or injectableorganic esters such as ethyl oleate may be used. The sterile aqueoussolutions can consist of a solution of the product in water. The acueoussolutions are suitable for intravenous administration provided the pH isappropriately adjusted and the solution is made isotonic, for examplewith a sufficient amount of sodium chloride or glucose. Thesterilization may be carried out by heating or by any other means whichdoes not adversely affect the composition. The combinations may alsotake the form of liposomes or the form of an association with carriersas cyclodextrins or polyethylene glycols.

The compositions for oral or intraperitoneal administration areDreferably aqueous suspensions or solutions.

In the combinations according to the invention, the application of theconstituents of which may be simultaneous, separate or spaced out over aperiod of time, it is especially advantageous for the amount of taxanederivative to represent from 10 to 90% by weight of the combination, itbeing possible for this content to vary in accordance with the nature ofthe associated substance, the efficacy sought and the nature of thecancer to be treated.

The combinations according to the invention are especially useful in thetreatment of cancers of the breast, ovary or lung. In particular, theycan afford the advantage of being able to employ the constituents atconsiderably lower doses than those at which they are used alone.

The example which follows illustrates a combination according to theinvention.

EXAMPLE

10-cm³ ampoules containing 100 mg of Taxotere are prepared, forintravenous administration, according to the usual technique.

5-cm³ ampoules containing 100 mg of etoposide are prepared, forintravenous administration, according to the usual technique.

These solutions are administered simultaneously, after appropriatedilution, by perfusion.

The treatment may be repeated several times daily or weakly until thereis a partial or total remission or a cure.

What is claimed is:
 1. A combination having therapeutic synergycomprising at least one taxane selected from the group consisting oftaxol, Taxotere and derivatives thereof in combination with an effectiveamount of a platinum coordination complex.
 2. The combination accordingto claim 1, wherein said platinum coordination complex is cisplatin. 3.The combination according to claim 1, further comprising one or moregrowth factors selected from the group consisting of G-CSF, GM-CSF andinterleukin.
 4. The combination according to claim 1, wherein said atleast one taxane is present in an amount ranging from 10% to 90% byweight.
 5. The combination according to claim 2 for the treatment ofmetastatic breast cancer.
 6. The combination according to claim 1,wherein said at least one taxane and said effective amount of a platinumcoordination complex are administered separately or simultaneously. 7.The combination according to claim 6, wherein each administrationcomprises a single dose or a continuous perfusion.
 8. The combinationaccording to claim 1, wherein said platinum coordination complex iscarboplatin.
 9. The combination according to claim 8, for the treatnentof metastatic breast cancer.